We have shown that acute viral infections are potent stimulators of a polyclonal CD8 T cell response, eliciting cytotoxic T lymphocytes (CTL) cross-reactive with alloantigens and with other viruses in mice and stimulating a CD8 T cell-dependent autoimmune diabetes in rats. We have also found that a heterologous viral infection may prime a CTL response and provide some protective immunity to a second viral infection, and that, subsequent to the second viral infection, the memory CTL response to the first is diminished. It is my belief that, at the clonal T cell level, there may be a great deal of immunological crossreactivity between serologically distinct infectious agents, and by virtue of this crossreactivity, the host's response to infection with a given pathogen may be a reflection of its previous history of infection with a whole panoply of theoretically unrelated infectious agents; this could lead to protective "natural" immunity or perhaps to more severe immunopathology. We envision an immunological network of memory cells that, by virtue of sometimes remote crossreactivities, are continually being modulated by infectious agents and other environmental antigens. We propose here to use several viruses and synthetic viral peptides to explore the specificities of virus-induced polyclonal CTL activation and to determine the significance of crossreactive CTL in "natural" resistance to infection, virus-induced immunopathology, virus-induced allograft rejection, and virus-induced autoimmunity. The primary model systems will be mice infected with lymphocytic choriomeningitis (LCMV), Pichinde, vaccinia, murine cytomegalo, and some other viruses. Specific Aim #1 will define the viral peptide and allospecificities of the CTL response to LCMV. Specific Aim #2 analyzes CTL responses crossreactive between different viruses. Specific Aim #3 tests several model systems for the significance of the crossreactive responses. Specific Aim #4 examines whether some T cells are either nonspecifically stimulated during infection or else stimulated in response to induced autoantigens.